Although several research groups all over the world are working to find highly selective PDE-4 isozyme inhibitors, so far success has been limited. Various compounds have shown PDE-4 inhibition. SmithKline Beecham's “Ariflo”, Byk Gulden's Roflumilast and Bayer's Bay-19-8004 have reached advanced stage of human clinical trials. Other compounds which have shown potent PDE-4 inhibitory activity include Celltech's CDP-840, Schering Plough's D-4418, Pfizer's 5CP-220,629, Parke Davis's PD-168787 and Wyeth's Filaminast. However, recently due to efficacy and side effects problems, Ariflo, CDP-840 and Bay-19-8004 were discontinued from clinical trials as a treatment for asthma. D-4418 and 5CP-220,629 are presently undergoing phase-1 clinical trials.
International Publication No. WO 2004/089940 discloses heterocyclic PDE-4 inhibitors, N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo-[b,d]furan-1-carboxamide and pharmaceutically acceptable salts thereof, useful in the treatment of certain allergic and inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD).
There remains a need for alternative methods for preparing N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide and pharmaceutically acceptable salts thereof.